Relapsing Plasmodium vivax malaria in a 12-year-old Brazilian girl: A case report

Plasmodium vivax causes the vast majority of malaria cases in Brazil. The lifecycle of this parasite includes a latent stage in the liver, the hypnozoite. Reactivation of hypnozoites induces repeated relapses. We report a case of two relapses of vivax malaria in a teenage girl after conventional treatment with chloroquine and primaquine. Chloroquine prophylactic treatment for three months was prescribed with a favourable outcome of the case.


INTRODUCTION
Malaria remains a major global public health problem, with a substantial increase in cases reported in the Americas in recent years, mainly in Brazil and Venezuela [1,2].In the Brazilian Amazon, most malaria cases are caused by Plasmodium vivax, a parasite that causes less severe disease compared to P. falciparum, but its biological characteristics present major challenges for current infection treatment and cure strategies [3,4].
In the last decades, the treatment of malaria made significant advances, providing a marked decrease in mortality worldwide.However, the elimination of P. vivax is hampered due to malaria relapses by activating hypnozoites, a population of sporozoites that undergo dormancy in hepatocytes.Hypnozoites are carried silently, with no symptoms.Reactivation of P. vivax hypnozoites from the dormant stage of the parasite causes clinical relapses.Hypnozoites causing relapses may be reactivated in as short as two weeks or as long as 10 months after the initial infection [5].In tropical climates, relapses occur at short intervals (3-4 weeks after treatment) [6].
The main factors involved in relapses are nonadherence to treatment, parasite resistance to drugs, poor drug quality or sub-therapeutic drug doses [7].Primaquine is the drug of choice for eliminating the hypnozoite form of the parasite [8].Until recently, primaquine was the only option for P. vivax liver-stage treatment.In 2018, following the regulatory approval of tafenoquine (a primaquine analogue with a half-life of approximately 15 days), this drug became an interesting alternative, especially because of the single-dose regimen reducing the risk of low or non-compliance [9,10].Both drugs are 8-aminoquinolines and need to be given with an appropriate blood stage drug to achieve radical cure [11,12].

CASE REPORT
A healthy 12-year-old female Brazilian patient was referred to the the Acute Febrile Diseases Reference Center (CPD-Mal) at the Instituto Nacional de Infectologia Evandro Chagas, Fiocruz (Rio de Janeiro, Brazil) with high fever, chills, severe headache, and mild diarrhoea.The patient reported having been diagnosed with P. vivax malaria (15 parasites/mm 3 ) on January 15th, 2021 in the local Reference Center during a consultation when she was living in the Brazilian Amazon.She was treated with a chloroquine and primaquine regimen, with correct drug dosage and treatment time.https://doi.org/10.5281/zenodo.11125657On May 13 th , 2021 (4 months after the first infection), a recurrence of P. vivax was diagnosed using a species-specific real time polymerase chain reaction (PCR) capable to detect submicroscopic parasitemias [13], as well as Abbot Pf/Pf/Pv RDT ® and thick blood smear (TBS); no P. falciparum or P. malariae mixed infections were detected by PCR [14,15].A new treatment with chloroquine and primaquine was prescribed according to the Brazilian treatment guidelines.The same malaria tests (PCR, RDT ® and TBS) were negative after this course of treatment.This new episode was considered a malaria relapse as the patient did not return to a malaria-endemic area and there was no epidemiological history to support the possibility of a new infection.
In July 2021 (6 months after the first infection), the patient developed high fever, chills, asthenia, and dyspnea.Again, the same PCR, RDT ® and TBS tests diagnosed a new relapse of P. vivax infection.Treatment with artesunate and mefloquine was recommended for this second relapse.The patient required hospitalisation and evolved with thrombocytopenia without bleeding episodes.Laboratory tests confirmed clinical cure after the therapeutic regimen.The patient was hospitalised for four days during the second recurrence that did not progress to clinical severity.She was discharged from the hospital with clinical and parasitological cure attested by parasite clearance through PCR, RDT ® and TBS clearance on July 29 th , 2021.In this second relapse, the patient had a much greater parasitaemia, predisposing to greater destruction of red blood cells, causing congestion in the spleen and producing platelet sequestration, justifying the transient thrombocytopenia.Table 1 shows the main laboratory tests performed during first and second relapses follow-up.
Subsequently, the patient received prophylactic treatment with chloroquine weekly for three months (July to October 2021) and after twelve months no malaria recurrence was detected by PCR, RDT ® and TBS.Table 2 shows the therapeutic regimens used during follow-up.

DISCUSSION
This case report demonstrated that infections with Brazilian isolates of P. vivax can relapse, despite adequate use of currently indicated drugs.Two relapses were documented within six months, raising doubts about the effectiveness of primaquine in eliminating the hypnozoite forms of the parasite (radical cure).Pina-Costa et al. [16] reported a series of three cases of malaria relapses, where an increase in primaquine dosage was attempted, but only two patients had satisfactory results.For the patient who did not respond to high doses of primaquine, prophylactic treatment with chloroquine (one weekly dose) was performed for three months, with radical cure.In our case, we tested Pina-Costa et al.'s recommendation and used chloroquine weekly for three months, achieving a radical cure of the parasite.
Chloroquine, artesunate, and mefloquine are effective drugs for treatment of blood stage P. vivax infections, and primaquine is routinely used for radical cure of hypnozoites [17].Achieving radical cure is the most significant therapeutic challenge in vivax malaria.
When Glucose-6-Phosphate Dehydrogenase (G6PD) status is normal, primaquine use is the gold standard of care [5].Our patient used the medica -Table 1. Laboratory tests and outcomes performed during P. vivax relapses in a 12-year-old girl from Brazil.https://doi.org/10.5281/zenodo.11125657tion regularly, with correct doses, and did not have G6PD deficiency.Since tafenoquine can only be prescribed for patients over 16 years old, even if the medicine would have been available, it was not eligible for the 12-year-old patient treatment.In this way, the treatment with primaquine was the only feasible option for managing the case.

CONCLUSION
A multitude of factors play a role in P. vivax recurrences, such as patient adherence to treatment, flawed treatment protocols, inadequate metabolism of primaquine, Plasmodium resistance to anti-malarial medications, and besides unknown factors.Managing cases of vivax malaria remains a complex challenge, necessitating healthcare professionals to closely adhere to guidelines in order to enhance treatment outcomes and reduce the impact/transmission of the disease.

Table 2 .
Therapeutic regimens used during recurrent P. vivax infections in a 12-year-old girl (bodyweight 49 kg) from Brazil.